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Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. Methods and design The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. Conclusions As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. Registration Number in ClinicalTrials.gov NCT05311072.

Abstract Background Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. Methods Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. Results Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. Conclusions Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

High and steep sandstone slopes along highway line are at high risk of disasters such as landslides, cracking of support structures, and so on. The monitoring, early warning, and emergency response of such slope disaster face enormous challenges, especially during the rainy season. In this paper, intelligent monitoring, early warning and forecasting system were carried out for the high steep sandstone slope with a transmission line tower at the slope crest along the highway under construction in Guangxi, China. The automatic monitoring data, emergency rescue program and rescue effect were analyzed, and emergency rescue measures for high steep slope protection were taken. The research results show that timely access to disaster warning information can effectively support the analysis of disaster causes and the evaluation of disposal programs. Deep-hole monitoring of deformation characteristics can determine the stable state of slopes, and the tangent angle warning criterion can be used for early warning and prediction of high steep slope landslides. By analyzing the location of the sliding surface and taking timely emergency disposal measures such as layered counterpressure method and micropipes, the landslide activities can be effectively controlled to prevent further acceleration of slope collapse. This study can provide an important reference for the monitoring, early warning, forecasting and emergency rescue of sandstone slopes along highways under construction.

Abstract Patients with venous thromboembolism (VTE) comorbid renal insufficiency (RI) are at higher risk of bleeding and thrombosis. Recommendations in guidelines on anticoagulation therapy for those patients remain ambiguous. The goal of this study is to compare the efficacy and safety between different anticoagulant regimens in VTE patients comorbid RI at different stages of treatment and prophylaxis. We performed English-language searches of Pubmed, EMBASE, and Web of Science (inception to Nov 2022). RCTs evaluated anticoagulants for VTE treatment at the acute phase, extension phase, and prophylaxis in patients with RI and reported efficacy and safety outcomes were selected. The methodological quality of the studies was assessed at the outcome level using the risk-of-bias assessment tool developed by the Cochrane Bias Methods Group. A meta-analysis of twenty-five RCTs was conducted, comprising data from twenty-three articles, encompassing a total of 9,680 participants with RI. In the acute phase, the risk of bleeding was increased with novel oral anticoagulants (NOACs) compared to LMWH (RR 1.29, 95% CI 1.04–1.60). For the prophylaxis of VTE, NOACs were associated with an elevated risk of bleeding compared with placebo (RR 1.31, 95%CI 1.02–1.68). In comparison to non-RI patients, both NOACs and vitamin K antagonists (VKA) could increase the risk of bleeding among RI patients (RR 1.45, 95%CI 1.14–1.84 and RR 1.53, 95%CI 1.25–1.88, respectively) during acute phase, while NOACs may increase the incidence of VTE in RI population (RR 1.74, 95%CI 1.29–2.34). RI patients who are under routine anticoagulation have a significantly higher risk of adverse outcomes. LMWH is the most effective and safe option for VTE treatment or prophylaxis in patients with RI.

Summary: Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p

Abstract Balloon pulmonary angioplasty (BPA) has been proven effective for addressing technically inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the effectiveness of BPA in technically operable CTEPH patients who, for various reasons, did not undergo the procedure remains an area requiring exploration. This study sought to assess the safety and efficacy of BPA in such cases. We collected and reviewed data from CTEPH patients who underwent BPA in a consecutive manner. Following multidisciplinary team (MDT) decisions, patients were classified into two groups: technically inoperable (group A) and operable (group B). Group B comprised patients deemed technically suitable for pulmonary endarterectomy (PEA) but who did not undergo the procedure for various reasons. All patients underwent a comprehensive diagnostic work‐up, including right heart categorization at baseline and the last intervention. This study compared changes in hemodynamic parameters, functional capacity, and quality of life between the two groups. In total, 161 patients underwent 414 procedures at our center, with Group A comprising 112 patients who underwent 282 BPA sessions and group B comprising 49 patients who underwent 132 BPA sessions. Significantly, both groups exhibited improvements in hemodynamics, functional capacity, and quality of life. The occurrence rate of complications, including hemoptysis and lung injury, was similar [12 (63.2%) vs. 7 (36.8%), p = 0.68]. BPA demonstrated favorable outcomes in patients with proximal CTEPH who did not undergo pulmonary endarterectomy. However, the clinical impact of BPA in technically operable CTEPH was found to be less significant than in inoperable cases.

Summary: Hematopoietic stem cells (HSCs) sustain hematopoiesis during homeostasis and regeneration. However, their limited availability poses a challenge for protein analysis. Here, we present a protocol for performing high-sensitivity western blot on HSCs using two techniques that enhance HSC isolation from mice and boost sensitivity for low cell numbers. We describe steps for isolating murine bone marrow cells, antibody staining, and cell sorting and post-sort analysis. We then detail a western blot procedure suitable for low numbers of HSCs.For complete details on the use and execution of this protocol, please refer to Li et al (2022).1,2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Topological quantum computation (TQC) is one of the most striking architectures that can realize fault-tolerant quantum computers. In TQC, the logical space and the quantum gates are topologically protected, i.e., robust against local disturbances. The topological protection, however, requires complicated lattice models and hard-to-manipulate dynamics; even the simplest system that can realize universal TQC—the Fibonacci anyon system—lacks a physical realization, let alone braiding the non-Abelian anyons. Here, we propose a disk model that can simulate the Fibonacci anyon system and construct the topologically protected logical spaces with the Fibonacci anyons. Via braiding the Fibonacci anyons, we can implement universal quantum gates on the logical space. Our disk model merely requires two physical qubits to realize three Fibonacci anyons at the boundary. By 15 sequential braiding operations, we construct a topologically protected Hadamard gate, which is to date the least-resource requirement for TQC. To showcase, we implement a topological Hadamard gate with two nuclear spin qubits, which reaches 97.18% fidelity by randomized benchmarking. We further prove by experiment that the logical space and Hadamard gate are topologically protected: local disturbances due to thermal fluctuations result in a global phase only. As a platform-independent proposal, our work is a proof of principle of TQC and paves the way toward fault-tolerant quantum computation.

【Objective】A comprehensive evaluation and prediction of ecological risks of cultivated land in Guangzhou City was carried out to effectively reveal the evolution relationship of between the pattern of cultivated land use and the ecological environment, with a view to serving the construction of ecological civilization in Guangzhou City.【Method】Based on the relative risk model, the study tried to construct a new index system for evaluating the ecological risks of cultivated land, which followed the main risk path of "problem formation-analysis stage -risk characterization-zoning prevention and control". And a comprehensive evaluation of the ecological risks of cultivated land in Guangzhou from 2000 to 2018 was conducted; with the data of various indicators of Guangzhou City at five-year intervals from 2000 to 2015 as initial values, the grey prediction model was used to forecast the ecological risks of cultivated land in the study area in 2020-2025. And corresponding measures to regulate and optimize the ecological risks of regional cultivated land were proposed.【Result】The ecological risk of cultivated land in Guangzhou was at lower risk status from 2000 to 2005, and the average indexes of the comprehensive evaluation of the ecological risk of cultivated land in 2000 and 2005 were 0.3327 and 0.3272, respectively; the ecological risk of cultivated land in Guangzhou was at low risk status from 2010 to 2018, and the average indexes for the comprehensive evaluation of the ecological risk of cultivated land in 2010, 2015 and 2018 were 0.3296, 0.3016 and 0.3078, respectively. Based on the comprehensive evaluation, the cultivated land of low risk- and lower risk- level held a dominant post, and the higher ecological risk areas (Zone Ⅳ) were mainly located in Tianhe District and Huangpu District, and the high ecological risk areas (Zone Ⅴ) located in northeastern of Baiyun District and northwestern of Huangpu District. The ecological risk level of cultivated land in Guangzhou will be at low risk status before 2025, with the predicted risk index of 0.2836.【Conclusion】Based on the above research results, the ecological risk status of cultivated land in Guangzhou shows an improving trend in the past study period, from the lower risk status in 2000-2005 to a low risk status in 2010-2018. In the short to medium term, the ecological risk status of cultivated land in Guangzhou will remain at a low risk level, and the relationship between natural environment, socio-economic development and landscape pattern of cultivated land should be continuously harmonized.

Abstract Noise is ubiquitous in real quantum systems, leading to non-Hermitian quantum dynamics, and may affect the fundamental states of matter. Here we report in an experiment a quantum simulation of the two-dimensional non-Hermitian quantum anomalous Hall (QAH) model using the nuclear magnetic resonance processor. Unlike the usual experiments using auxiliary qubits, we develop a stochastic average approach based on the stochastic Schrödinger equation to realize the non-Hermitian dissipative quantum dynamics, which has advantages in saving the quantum simulation sources and simplifying the implementation of quantum gates. We demonstrate the stability of dynamical topology against weak noise and observe two types of dynamical topological transitions driven by strong noise. Moreover, a region where the emergent topology is always robust regardless of the noise strength is observed. Our work shows a feasible quantum simulation approach for dissipative quantum dynamics with stochastic Schrödinger equation and opens a route to investigate non-Hermitian dynamical topological physics.

Fiber reinforcement is the most common method for modifying polylactic acid (PLA). However, poor compatibility between fibers and PLA, especially at high cellulose contents, can promote cellulose agglomeration in the continuous phase, which damages the mechanical properties of composite materials. To address these issues, bagasse cellulose (BC) was used as a substrate and bifunctional glycidyl methacrylate (GMA) was used as a reactive monomer for graft modification. GMA-modified BC (BC-GMA)/PLA composite materials with different particle sizes were prepared using a blending grafting method, and the influence of the type and content of BC-GMA on the mechanical properties of the composite materials was explored. During the grafting modification of BC, a longer reaction time was found to result in smaller BC particles and a higher degree of grafting. For BC-GMA, the degree of grafting reached 27.02% with a maximum thermal decomposition temperature of 359.31°C. Furthermore, the BC-GMA/PLA composite material had a greater relative crystallinity of PLA, indicating that BC-GMA was evenly dispersed in the continuous phase. This study demonstrates that grafting modification can successfully achieve high cellulose loading in composite materials and thus reduce the production costs of PLA-based packaging materials.

Abstract Chimeric antigen receptor (CAR)‐T cell therapy is a transformative treatment against advanced malignancies. Unfortunately, once administrated in vivo, CAR‐T cells become out of artificial control, and fierce response to CAR‐T therapy may cause severe adverse events, represented by cytokine‐release syndrome and on‐target/off‐tumor effects. Here, a nanomodified switch strategy is developed, leading to sustained and precise “on‐tumor only” activation of CAR‐T cells. Here, original gelatinase‐responsive nanoparticles (NPs) are used to selectively deliver the heterodimerizing switch, which is the key component of switchable CAR with separated activation modules. The “NanoSwitch” is tumor‐specific, thus inactivated switchable CAR‐T cells do little harm to normal cells, even if the normal cells express the target of CAR‐T. Owing to the sustained‐release effect of NPs, the CAR‐T cells are activated smoothly, avoiding sudden release of cytokine. These data introduce NanoSwitch as a universal and applicable solution to safety problems of CAR‐T therapy regardless of the target.

Satellite-based soil moisture products allow direct monitoring of agricultural drought, especially in regions with sparse ground-based observations. In this study, a soil moisture drought index only based on satellite soil moisture is developed and adopted to assess drought in Mainland Southeast Asia (MSA). We report here on an exceptionally severe Mainland Southeast Asia drought in 2016, which is believed to be strongly linked to the 2015–2016 super El Niño strongly. The event began in February 2016 and lasted until May 2016, with more than 50% of the study areas suffering from moderate drought or worse at peak period. We assess the evolution of agricultural droughts (defined as prolonged deficit in soil moisture) by placing it in the context of the forcing meteorological drought (prolonged deficit in precipitation). The drought assessment using satellite soil moisture is temporally consistent with precipitation-based metrics, but allows for better mapping of the spatial and temporal patterns of how a precipitation deficit may or may not lead to a soil moisture deficit. The specific advantages of a remote-sensing approach—wide-coverage without need for spatially-dense, ground-based climatological records, and sensitivity to otherwise unmeasured irrigation inputs—suggest further opportunity for drought monitoring in ungauged regions, particularly in agricultural contexts.

Breast cancer is considered a malignant tumor with the highest incidence among women and is prone to develop distant metastasis. Small intestinal metastasis of breast cancer, however, is relatively rare. This case report describes a 49-year-old Chinese female patient who presented with small intestinal obstruction and was diagnosed with lobular breast cancer with small intestinal and contralateral breast metastasis. Clinical manifestations, clinicopathological features and potential mechanisms of metastasis, along with diagnosis and treatment, are discussed with a review of the relevant literature. Although small intestinal metastasis is rare in breast cancer, we should keep high alert on the possibility of gastrointestinal metastasis when treating lobular breast cancer patients.

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) patients may present with atherosclerotic lesions in their pulmonary arteries, but their clinical characteristics remain unclear. The metabolic pathways associated with the atherosclerotic lesions may explain their occurrence and have implications for interventions, but they have not been investigated.MethodsWe collected pulmonary endarterectomy (PEA) samples of CTEPH patients from December 2016 to August 2021. Following a detailed pathological examination of the PEA specimen, the patients were divided into those with and without lesions, and age- and sex matching were performed subsequently using propensity score matching (n = 25 each). Metabolomic profiling was used to investigate the metabolites of the proximal lesions in the PEA specimens.ResultsIn our study population, 27.2% of all PEA specimens were found to contain atherosclerotic lesions. CTEPH patients with atherosclerotic lesions were more likely to have a history of symptomatic embolism and had a longer timespan between embolism and surgery, whereas the classic risk factors of systemic and coronary circulation could not distinguish CTEPH patients with or without atherosclerotic lesions. Metabolomic profiling revealed that the formation of atherosclerotic lesions in CTEPH was closely related to altered glycine, serine, and threonine metabolic axes, possibly involved in cellular senescence, energy metabolism, and a proinflammatory microenvironment.ConclusionThe occurrence of atherosclerotic lesions in the pulmonary arteries of CTEPH was associated with symptomatic thromboembolic history and prolonged disease duration. The results revealed a new link between atherosclerotic lesions and aberrant amino acid metabolism in the context of CTEPH for the first time. This study has characterized the clinical and metabolic profiles of this distinct group of CTEPH patients, providing new insights into disease pathogenesis and potential interventions.

BackgroundCell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive.MethodsWe extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance.ResultsOur scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells.ConclusionsLeukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.

P2ry12 is a microglial marker gene. Recently, increasing evidence has demonstrated that its expression levels can vary in response to different CNS disorders and can affect microglial functions, such as polarization, plasticity, and migration. However, the expression and function of P2ry12 in microglia during ischemia–reperfusion injury (IRI) remain unclear. Here, we developed a computational method to obtain microglia-specific P2ry12 genes (MSPGs) using sequencing data associated with IRI. We evaluated the change in comprehensive expression levels of MSPGs during IRI and compared it to the expression of P2ry12 to determine similarity. Subsequently, the MSPGs were used to explore the P2ry12 functions in microglia through bioinformatics. Moreover, several animal experiments were also conducted to confirm the reliability of the results. The expression of P2ry12 was observed to decrease gradually within 24 h post injury. In response, microglia with reduced P2ry12 expression showed an increase in the expression of one receptor-encoding gene (Flt1) and three ligand-encoding genes (Nampt, Igf1, and Cxcl2). Furthermore, double-labeling immunofluorescence staining revealed that inhibition of P2ry12 blocked microglial migration towards vessels during IRI. Overall, we employ a combined computational and experimental approach to successfully explore P2ry12 expression and function in microglia during IRI.

Terrestrial vegetation response to surface water availability is important for land–atmosphere interactions. However, the current understanding of how the vegetation responds to surface water remains limited since the physical processes happening within the biosphere and hydrosphere are highly coupled. It is even more difficult to measure such interactions for the processes related to surface soil moisture (SSM)—the central variable that interacts the most intimately with vegetation—since the observations of SSM are often scarce and uneven. Here, we use the satellite observations of vegetation optical depth (VOD) and SSM to map the response time scales of vegetation to surface water anomalies. We use the stability theory to derive vegetation memory time (${{{\bf \tau }}_{{{\bf ReS}}}}$) to reveal the global pattern of vegetation memory to surface water anomalies. That is, the time vegetation takes to return back to its equilibrium when an anomaly dissipates to a certain level (e.g., the e-folding level). We also estimate the plant reactive time (${{{\bf \tau }}_{{{\bf ReA}}}}$)—the time when impacts of surface anomaly reach its peak to evaluate the overall resilience of terrestrial vegetation to surface water anomalies. The results show that ${{{\bf \tau }}_{{{\bf ReS}}}}$ tends to be longer in herbaceous biomes, whereas ${{{\bf \tau }}_{{{\bf ReA}}}}$ is longer in biomes with tree cover. Such anticorrelation of ${{{\bf \tau }}_{{{\bf ReS}}}}$ and ${{{\bf \tau }}_{{{\bf ReA}}}}$ indicates that the herbaceous biomes may be more vulnerable to surface water perturbations during climate extremes. Our study provides a global quantification on vegetation—soil moisture feedbacks—enabling comparison with earth system models.

Abstract Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting‐therapy efficacy remains unexplored. Here, an L‐phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T‐cell acute lymphoblastic leukemia (T‐ALL) by inhibiting myeloid‐derived suppressor cells (MDSCs) in T‐ALL murine model. Stable‐isotope tracer and in vivo drug distribution experiments show that T‐ALL cells and MDSCs have enhanced cellular uptake of L‐phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN‐Dox) specifically targets T‐ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN‐Dox has reduced cardiotoxicity and myeloablation side effects in treating T‐ALL mice. Mechanistically, MRIAN degrades into L‐phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T‐ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

Hepatocellular carcinoma (HCC) has a poor prognosis due to the rapid disease progression and early metastasis. The metabolism program determines the proliferation and metastasis of HCC; however, the metabolic approach to treat HCC remains uncovered. Here, by analyzing the liver cell single-cell sequencing data from HCC patients and healthy individuals, we found that 6-phosphogluconolactonase (PGLS), a cytosolic enzyme in the oxidative phase of the pentose phosphate pathway (PPP), expressing cells are associated with undifferentiated HCC subtypes. The Cancer Genome Atlas database showed that high PGLS expression was correlated with the poor prognosis in HCC patients. Knockdown or pharmaceutical inhibition of PGLS impaired the proliferation, migration, and invasion capacities of HCC cell lines, Hep3b and Huh7. Mechanistically, PGLS inhibition repressed the PPP, resulting in increased reactive oxygen species level that decreased proliferation and metastasis and increased apoptosis in HCC cells. Overall, our study showed that PGLS is a potential therapeutic target for HCC treatment through impacting the metabolic program in HCC cells.

Applying gel-type solid chlorine dioxide for the sustained release of chlorine dioxide has several shortcomings, such as no resistance to acid and alkali corrosion and poor mechanical properties. However, introducing quaternary ammonium, carboxyl, and amino groups into the hydrogel system can enhance its acid and alkali resistance. In this study, the effects of concentration of dry heat-modified starch, quaternized carboxymethyl cellulose, and chitin on the swelling behavior and mechanical properties of starch-based acid- and alkali-resistant hydrogels are investigated. The feasibility of the actual and predicted values of the tentative results is verified based on the response surface design to determine the optimal concentration ratio of acid- and alkali-resistant hydrogels. The results reveal that optimized process parameters are reliable. The maximum swelling ratio and compressive stress of the hydrogel are 5358.00% and 44.45 kPa, respectively, and its swelling behavior conforms to the pseudo second-order kinetic model. Thus, the present study can provide a new method of developing efficient starch-based chlorine dioxide hydrogels for the sustained release of chlorine dioxide.

Study Region Mekong River Basin and surrounding areas. Study Focus: This study investigated the impacts of climate change on future meteorological and hydrological droughts in the Mekong River Basin and its surrounding areas. Our work is based on the output of five global climate models (GCMs) and simulations using the geomorphology-based hydrological model (GBHM) for the historical (1975–2004), near future (2010–2039), middle future (2040–2069), and far future (2070–2099) periods. The meteorological droughts in the study area were measured using SPI and SPEI, while the hydrological droughts were measured using SSI. New Hydrological Insights for the Region: The results suggest that droughts will generally reduce in the future over most of the study area, but will be more unevenly distributed with an eastward migration as compared to the historical period. Both meteorological and hydrological droughts will intensify in the near future, but will then reduce in intensity. Meteorological droughts will increase in the northeastern areas in the near future, followed by migration towards the south. Hydrological droughts showed similar aggravation followed by reduction, with upstream areas showing greater variability. In the general context of drought alleviation, southwestern China and the Mekong River estuary may suffer from a continuously increasing drought intensity in the future. This finding is based on 100-year extreme drought events.

Cost-effective, practical, and efficiently performing photosensitive resin composite materials are essential, as the current materials are expensive, lack better alternatives, and do not meet 3D printing standards. In this study, based on orthogonal experiments for photosensitive resin curing, we prepared a free-radical/cationic hybrid photosensitive UV cured resin (UVR) using acrylic ester and epoxy resin as the prepolymers, tripropylenediol diacrylate (TPGDA) as the active diluent, and triaryl sulfonium salt (I-160) and 2,2-dimethyl-α-hydroxy acetophenone (1173) as the photoinitiators, in the optimized formula of acrylic-ester:epoxy-resin:TPGDA:I-160:1173 = 37.5:37.5:20:2.5:2.5. Further, we investigated the effects of polyurethane acrylates (PUA) and Graphene oxide (GO) on the surface morphology, chemical structure, hydrophobicity, mechanical strength, and gelation rate of the hybrid resin. We observed that 20% PUA improved tensile strength to the maximum of 36.89 MPa from 16.42 MPa of the unmodified hybrid resin, whereas 1% GO reduced volume shrinkage to the minimum of 2.89% from 3.73% of the unmodified hybrid resin. These photosensitive resins with higher tensile strength and lower volume shrinkage can be used to synthesize high performance functional materials in the future.

Based on the daily precipitation data of 2, 424 stations and conventional weather chart data in mainland China in 2021, a statistical analysis of the main heavy rain weather processes from April to October of that year was conducted. The main influencing systems and precipitation situations were outlined, and a comparative analysis of the number of heavy rain days and major heavy rain events from 2008 to 2021 from April to October was performed. The results show that from April to October 2021, China experienced a total of 199 heavy rain days and 32 major heavy rain events. The number of heavy rain days was 10 days more than the average for the previous 13 years (2008-2020), while the number of major heavy rain events remained the same as the average for the previous 13 years. Among them, there were 7 occurrences in July, 6 in May and August each, 5 in June, 4 in September, and 3 in October, with 1 occurrence in April. Among the 32 major heavy rain events, 5 were caused by the landing or influence of tropical cyclones. The northern heavy rain from July 18th to 22nd, including the "7.20" extreme heavy rain in Zhengzhou, was the most widely affected and economically damaging major heavy rain event, with Zhengzhou in Henan Province recording the country's largest daily precipitation of 552.5 mm on July 20th of that year. The maximum accumulated rainfall for a single event in the year reached 820 mm, also occurring in Zhengzhou, Henan Province (July 18th to 22nd) and was caused by the joint influence of a trough, shear line, and warm and humid airflow.

Abstract Background Reports on coronavirus disease 2019 (COVID-19) in neonates are limited, especially in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) Omicron variant. This study aims to analyze the clinical characteristics and identify risk factors associated with severe COVID-19 in neonates infected with Omicron variant. Methods The study population was represented by neonates with COVID-19, who were admitted to The Affiliated Children’s Hospital of Xi’an Jiaotong University in northwest China, from December 10, 2022 to January 20, 2023. Chinese Center for Disease Control and Prevention (CDC) announced that all local COVID-19 cases were infected with Omicron variant during the study period. Clinical and laboratory data were collected retrospectively. We used logistic regression analysis to investigate the risk factors for severe COVID-19, and derived odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Results A total of 108 neonates, with median age of 18.1 days (interquartile range 9.4–23.0), were affected by COVID-19, of whom 84 had a mild disease, while 24 a severe one (22.2%). Of them, 6.5% were premature. No deaths were observed in the study population. The most common clinical manifestations were fever (88.9%) and cough (55.6%), with 5 cases (4.6%) complicated by pneumonia. 4 cases (3.7%) received respiratory support, including 2 cases of high-flow oxygen and 2 cases of continuous positive airway pressure. Gestational age at birth (OR: 0.615; 95% CI: 0.393–0.961), neutrophil count (NEU) (OR:0.576; 95% CI : 0.344–0.962) and lymphocyte count (LYM) (OR: 0.159; 95% CI: 0.063–0.401) were independent risk factors for severe COVID-19. The combination of NEU and LYM had the largest receiver operating characteristic area under the curve [0.912 (95% CI:0.830–0.993)] for identifying severe COVID-19, with a sensitivity of 0.833 and a specificity of 0.917. Conclusions The general presentations and outcomes of neonatal COVID-19 caused by Omicron variant were not severe, and very few patients required respiratory support. The simultaneous decrease in NEU and LYM can be used to identify severe infection.

Abstract Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy.

In this work, the mechanical principles of external fixation and resistance training for the wrist affected by a distal radius fracture (DRF) are revealed. Based on the biomechanical analysis, two wearable exoskeleton devices are proposed to facilitate the DRF rehabilitation progress. Chronologically, the adjustable fixation device (AFD) provides fixed protection and limited mobilization of the fractured wrist in the early stage, while the functional recovery of relevant muscles is achieved by the resistance training device (RTD) in the later stage. According to the designed mechatronic systems of AFD and RTD, the experimental prototypes for these two apparatuses are established. By experiments, the actual motion ranges of AFD are investigated, and the feasibility in monitoring joint angles are validated. Meanwhile, the resistant influences of RTD are analyzed based on the surface electromyography (sEMG) signal features, the results demonstrate that the training-induced muscle strength enhancement is generally increased with the increment in external resistance. The exoskeleton devices presented in this work would be beneficial for the active rehabilitation of patients with DRF.

Abstract Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer (LARC) patients with microsatellite stable (MSS) / mismatch repair-proficient (pMMR) tumors is an attractive, but debatable strategy. This phase 2, multicenter, prospective, single-arm study enrolled patients from 6 centers from June 2021 to November 2022. Locally advanced rectal cancer (LARC, cT3-4aN0M0 and cT1-4aN1-2M0) patients aged ≥18 years with the distance from distal border of tumor to anal verge ≤10 cm (identified by Magnetic Resonance Imaging) were qualified for inclusion. The patients received long-course radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week) and three 21-day cycles capecitabine (850–1000 mg/m2, bid, po, day1–14) and three 21-day cycles tislelizumab (200 mg, iv.gtt, day8) as neoadjuvant. Total mesorectal excision (TME) was 6–12 weeks after the end of radiotherapy to achieve radical resection. A total of 50 patients were enrolled in this study. The pathological complete response rate was 40.0% [20/50, 95% confidence interval (CI): 27.61–53.82%], while 15 (30.0%, 95% CI: 19.1–43.75%), 9 (18.0%, 95% CI: 9.77–30.8%), 2 (4.0%, 95% CI: 1.10–13.46%) patients respectively achieved grade 1, 2, and 3 tumor regression. Treatment-related adverse events (TRAEs) occurred in 28 (56.0%) LARC patients, including 26(52.0%) with grade I-II and 2 (4.0%) with grade III (1 with grade 3 immune-related colitis and 1 with grade 3 rash). PD-1 blockade plus long-course chemoradiotherapy (CRT) showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients. A larger randomized controlled study is desired to further validate the above findings.

Abstract Background During the pandemic, a notable increase in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), conditions that warrant emergent management, was reported. We aimed to investigate the trend of DKA‐ and HHS‐related mortality and excess deaths during the pandemic. Methods Annual age‐standardized mortality rates related to DKA and HHS between 2006 and 2021 were estimated using a nationwide database. Forecast analyses based on prepandemic data were conducted to predict the mortality rates during the pandemic. Excess mortality rates were calculated by comparing the observed versus predicted mortality rates. Subgroup analyses of demographic factors were performed. Results There were 71 575 DKA‐related deaths and 8618 HHS‐related deaths documented during 2006–2021. DKA, which showed a steady increase before the pandemic, demonstrated a pronounced excess mortality during the pandemic (36.91% in 2020 and 46.58% in 2021) with an annual percentage change (APC) of 29.4% (95% CI: 16.0%–44.0%). Although HHS incurred a downward trend during 2006–2019, the excess deaths in 2020 (40.60%) and 2021 (56.64%) were profound. Pediatric decedents exhibited the highest excess mortality. More than half of the excess deaths due to DKA were coronavirus disease 2019 (COVID‐19) related (51.3% in 2020 and 63.4% in 2021), whereas only less than a quarter of excess deaths due to HHS were COVID‐19 related. A widened racial/ethnic disparity was observed, and females exhibited higher excess mortality than males. Conclusions The DKA‐ and HHS‐related excess mortality during the pandemic and relevant disparities emphasize the urgent need for targeted strategies to mitigate the escalated risk in these populations during public health crises.

BackgroundWe aimed to determine the trend of TB-related deaths during the COVID-19 pandemic.MethodsTB-related mortality data of decedents aged ≥25 years from 2006 to 2021 were analyzed. Excess deaths were estimated by determining the difference between observed and projected mortality rates during the pandemic.ResultsA total of 18,628 TB-related deaths were documented from 2006 to 2021. TB-related age-standardized mortality rates (ASMRs) were 0.51 in 2020 and 0.52 in 2021, corresponding to an excess mortality of 10.22 and 9.19%, respectively. Female patients with TB demonstrated a higher relative increase in mortality (26.33 vs. 2.17% in 2020; 21.48 vs. 3.23% in 2021) when compared to male. Female aged 45–64 years old showed a surge in mortality, with an annual percent change (APC) of −2.2% pre-pandemic to 22.8% (95% CI: −1.7 to 68.7%) during the pandemic, corresponding to excess mortalities of 62.165 and 99.16% in 2020 and 2021, respectively; these excess mortality rates were higher than those observed in the overall female population ages 45–64 years in 2020 (17.53%) and 2021 (33.79%).ConclusionThe steady decline in TB-related mortality in the United States has been reversed by COVID-19. Female with TB were disproportionately affected by the pandemic.

Accurately predicting the production rate and estimated ultimate recovery (EUR) of shale oil wells is vital for efficient shale oil development. Although numerical simulations provide accurate predictions, their high time, data, and labor demands call for a swifter, yet precise, method. This study introduces the Duong–CNN–LSTM (D-C-L) model, which integrates a convolutional neural network (CNN) with a long short-term memory (LSTM) network and is grounded on the empirical Duong model for physical constraints. Compared to traditional approaches, the D-C-L model demonstrates superior precision, efficiency, and cost-effectiveness in predicting shale oil production.

Abstract The severity of heat stroke (HS) is associated with intestinal injury, which is generally considered an essential issue for HS. Heat acclimation (HA) is considered the best strategy to protect against HS. In addition, HA has a protective effect on intestinal injuries caused by HS. Considering the essential role of gut microbes in intestinal structure and function, we decided to investigate the potential protective mechanism of HA in reducing intestinal injury caused by HS. HA model was established by male C57BL/6J mice (5–6 weeks old, 17–19 g) were exposed at (34 ± 0.7)°C for 4 weeks to establish an animal HA model. The protective effect of HA on intestinal barrier injury in HS was investigated by 16S rRNA gene sequencing and nontargeted liquid chromatography‐mass spectrometry (LC‐MS) metabolomics. According to the experimental results, HA can change the composition of the gut microbiota, which increases the proportion of lactobacilli, faecal bacteria, and urinobacteria but decreases the proportion of deoxycholic acid. Moreover, HA can reduce liver and kidney injury and systemic inflammation caused by HS and reduce intestinal injury by enhancing the integrity of the intestinal barrier. In addition, HA regulates inflammation by inhibiting NF‐κB signalling and increasing tight junction protein expression in HS mice. HA induces changes in the gut microbiota, which may enhance tight junction protein expression, thereby reducing intestinal inflammation, promoting bile acid metabolism, and ultimately maintaining the integrity of the intestinal barrier. In conclusion, HA induced changes in the gut microbiota. Among the gut microbiota, lactobacilli may play a key role in the potential protective mechanism of HA.